Causes and impact of delays during the COVID-19 pandemic on head and neck cancer diagnosis.

BACKGROUND: The causes for delays during the COVID19 pandemic and their impact on head and neck cancer (HNC) diagnosis and staging are not well described. METHODS: Two cohorts were defined a priori for review and analysis-a Pre-Pandemic cohort (June 1 to December 31, 2019) and a Pandemic cohort (June 1 to December 31, 2020). Delays were categorized as COVID-19 related or not, and as clinician, patient, or policy related. RESULTS: A total of 638 HNC patients were identified including 327 in the Pre-Pandemic Cohort and 311 in the Pandemic Cohort. Patients in the Pandemic cohort had more N2-N3 category (41% vs. 33%, p = 0.03), T3-T4 category (63% vs. 50%, p = 0.002), and stage III-IV (71% vs. 58%, p < 0.001) disease. Several intervals in the diagnosis to treatment pathway were significantly longer in the pandemic cohort as compared to the Pre-Pandemic cohort. Among the pandemic cohort, 146 (47%) experienced a delay, with 112 related to the COVID-19 pandemic; 80 (71%) were clinician related, 15 (13%) were patient related, and 17 (15%) were policy related. CONCLUSIONS: Patients in the Pandemic cohort had higher stage disease at diagnosis and longer intervals along the diagnostic pathway, with COVID-19 related clinician factors being the most common cause of delay.

Transoral Robotic Surgery and Radiation Volume Deintensification in Unknown Primary Squamous Cell Carcinoma of the Neck: The Phase 2 FIND Nonrandomized Controlled Trial.

Importance: Patients with unknown primary squamous cell carcinoma (CUP) with cervical metastases typically receive comprehensive radiotherapy (RT) of the pharynx and bilateral neck. Typically, these patients receive comprehensive RT of the pharynx and bilateral neck that may produce treatment-related toxic effects. Objective: To determine whether localization of occult oropharyngeal cancers with transoral robotic surgery (TORS) combined with reduced pharyngeal and neck RT volumes provides acceptable disease control. Design, Setting, and Participants: This phase 2, single-group nonrandomized controlled trial at a single institution accrued 32 prospective participants with p16-positive CUP without a primary squamous cell carcinoma on examination and imaging from 2017 to 2019, and 24-month follow-up. The data analysis was conducted from January 2021 to June 2022. Intervention: Diagnostic- (n = 13) or therapeutic-intent (n = 9) TORS, with pharyngeal-sparing radiotherapy (PSRT) prescribed for negative margins or pT0, and unilateral neck RT (UNRT) prescribed for unilateral lymphadenopathy with lateralized primary tumor or pT0. Main Outcomes and Measures: Out-of-radiation treatment volume failure (<15% was hypothesized to be acceptable) and reports of local and regional recurrence, overall survival, toxic effects, swallowing outcomes (per the MD Anderson Dysphagia Inventory), and videofluoroscopic swallow (per Dynamic Imaging Grade of Swallowing Toxic Effects [DIGEST]) ratings. Results: The study sample comprised 22 patients (mean [SD] age, 59.1 [5.7] years; 3 [14%] females and 19 [86%] male) with CUP. Of these, 19 patients (86%) had tumor stage cN1; 2 (9%), cN2; and 1 (5%), cN3. Five patients (23%), 14 patients (64%), and 3 patients (13%) had 0, 1, or 2 primary tumors, respectively. Twenty patients received RT; of these, 9 patients (45%) underwent PSRT and 10 patients (50%), UNRT. In the diagnostic-intent group, 8 patients (62%) and 5 patients (38%) underwent RT and RT-concurrent chemotherapy, respectively. In the therapeutic-intent group, 6 patients (67%) and 1 patient (11%) received adjuvant RT-concurrent chemotherapy, respectively; 2 patients declined RT. Two-year out-of-radiation treatment volume failure, locoregional control, distant metastasis control, and overall survival were 0%, 100%, 95%, and 100%, respectively. Grade 3 or 4 surgical, acute, and late toxic effects occurred in 2 (9%), 5 (23%), and 1 (5%) patients, respectively. PSRT was associated with lower RT dose to superior constrictors (37 vs 53 Gy; mean difference, 16 Gy; 95% CI, 6.4, 24.9), smaller decline in swallowing scores during treatment (19.3 vs 39.7; mean difference, -20.4; 95% CI, -34.1 to -6.1), and fewer patients with worsening DIGEST grade on findings of videofluoroscopic swallow studies at 2 years (0% vs 60%; difference, 60%; 95% CI, 30% to 90%). Conclusions and Relevance: These findings indicate that TORS for p16-positive CUP allows RT volume deintensification with excellent outcomes and support future investigation in randomized clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT03281499.

Telemedicine-enabled biofeedback electropalatography rehabilitation (TEBER): A pilot study for patients treated with surgery for oral cavity carcinoma.

BACKGROUND: To address the rehabilitative barriers to frequency and precision of care, we conducted a pilot study of a biofeedback electropalatography (EPG) device paired with telemedicine for patients who underwent primary surgery +/- adjuvant radiation for oral cavity carcinoma. We hypothesized that lingual optimization followed by telemedicine-enabled biofeedback electropalatography rehabilitation (TEBER) would further improve speech and swallowing outcomes after "standard-of-care" SOC rehabilitation. METHOD: Pilot prospective 8-week (TEBER) program following 8 weeks of (SOC) rehabilitation. RESULTS: Twenty-seven patients were included and 11 completed the protocol. When examining the benefit of TEBER independent of standard of care, "range-of-liquids" improved by +0.36 [95% CI, 0.02-0.70, p = 0.05] and "range-of-solids" improved by +0.73 [95% CI, 0.12-1.34, p = 0.03]. There was a positive trend toward better oral cavity obliteration; residual volume decreased by -1.2 [95% CI, -2.45 to 0.053, p = 0.06], and "nutritional-mode" increased by +0.55 [95% CI, -0.15 to 1.24, p = 0.08]. CONCLUSION: This pilot suggests that TEBER bolsters oral rehabilitation after 8 weeks of SOC lingual range of motion.

Pembrolizumab plus concurrent chemoradiotherapy versus placebo plus concurrent chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (KEYNOTE-412): a randomised, double-blind, phase 3 trial.

BACKGROUND: Despite multimodal therapy, 5-year overall survival for locally advanced head and neck squamous cell carcinoma (HNSCC) is about 50%. We assessed the addition of pembrolizumab to concurrent chemoradiotherapy for locally advanced HNSCC. METHODS: In the randomised, double-blind, phase 3 KEYNOTE-412 trial, participants with newly diagnosed, high-risk, unresected locally advanced HNSCC from 130 medical centres globally were randomly assigned (1:1) to pembrolizumab (200 mg) plus chemoradiotherapy or placebo plus chemoradiotherapy. Randomisation was done using an interactive response technology system and was stratified by investigator's choice of radiotherapy regimen, tumour site and p16 status, and disease stage, with participants randomly assigned in blocks of four per stratum. Participants, investigators, and sponsor personnel were masked to treatment assignments. Local pharmacists were aware of assignments to support treatment preparation. Pembrolizumab and placebo were administered intravenously once every 3 weeks for up to 17 doses (one before chemoradiotherapy, two during chemoradiotherapy, 14 as maintenance therapy). Chemoradiotherapy included cisplatin (100 mg/m2) administered intravenously once every 3 weeks for two or three doses and accelerated or standard fractionation radiotherapy (70 Gy delivered in 35 fractions). The primary endpoint was event-free survival analysed in all randomly assigned participants. Safety was analysed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03040999, and is active but not recruiting. FINDINGS: Between April 19, 2017, and May 2, 2019, 804 participants were randomly assigned to the pembrolizumab group (n=402) or the placebo group (n=402). 660 (82%) of 804 participants were male, 144 (18%) were female, and 622 (77%) were White. Median study follow-up was 47·7 months (IQR 42·1-52·3). Median event-free survival was not reached (95% CI 44·7 months-not reached) in the pembrolizumab group and 46·6 months (27·5-not reached) in the placebo group (hazard ratio 0·83 [95% CI 0·68-1·03]; log-rank p=0·043 [significance threshold, p≤0·024]). 367 (92%) of 398 participants treated in the pembrolizumab group and 352 (88%) of 398 participants treated in the placebo group had grade 3 or worse adverse events. The most common grade 3 or worse adverse events were decreased neutrophil count (108 [27%] of 398 participants in the pembrolizumab group vs 100 [25%] of 398 participants in the placebo group), stomatitis (80 [20%] vs 69 [17%]), anaemia (80 [20%] vs 61 [15%]), dysphagia (76 [19%] vs 62 [16%]), and decreased lymphocyte count (76 [19%] vs 81 [20%]). Serious adverse events occurred in 245 (62%) participants in the pembrolizumab group versus 197 (49%) participants in the placebo group, most commonly pneumonia (43 [11%] vs 25 [6%]), acute kidney injury (33 [8%] vs 30 [8%]), and febrile neutropenia (24 [6%] vs seven [2%]). Treatment-related adverse events led to death in four (1%) participants in the pembrolizumab group (one participant each from aspiration pneumonia, end-stage renal disease, pneumonia, and sclerosing cholangitis) and six (2%) participants in the placebo group (three participants from pharyngeal haemorrhage and one participant each from mouth haemorrhage, post-procedural haemorrhage, and sepsis). INTERPRETATION: Pembrolizumab plus chemoradiotherapy did not significantly improve event-free survival compared with chemoradiotherapy alone in a molecularly unselected, locally advanced HNSCC population. No new safety signals were seen. Locally advanced HNSCC remains a challenging disease that requires better treatment approaches. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Long-term Outcomes of Bevacizumab and Chemoradiation for Locoregionally Advanced Nasopharyngeal Carcinoma: A Nonrandomized Controlled Trial.

Importance: The long-term outcomes associated with adding bevacizumab, a vascular endothelial growth factor inhibitor, to standard chemoradiation have continued to be favorable for a group of patients with locoregionally advanced nasopharyngeal carcinoma (NPC). Objective: To assess long-term toxic effects and clinical outcomes associated with chemotherapy, radiation therapy (RT), and bevacizumab for NPC. Design, Setting, and Participants: This single-arm phase II nonrandomized controlled trial was conducted by the National Cancer Trials Network group and NRG Oncology (formerly Radiation Therapy Oncology Group), with accrual from December 13, 2006, to February 5, 2009, and data analysis from June 26 to July 1, 2019. The study was conducted at 19 cancer centers with a median (IQR) follow-up of 9.0 (7.7-9.3) years. Included patients were adults (aged ≥18 years) with NPC that was World Health Organization (WHO) histologic grade I to IIb or III, American Joint Committee on Cancer stage IIB or greater, and with or without lymph node involvement. Interventions: Patients received 3 cycles of bevacizumab (15 mg/kg) concurrently with standard cisplatin (100 mg/m2) and RT (69.96 Gy) followed by 3 cycles of adjuvant bevacizumab (15 mg/kg) given concurrently with cisplatin (80 mg/m2) and fluorouracil (1000 mg/m2/d). Main Outcomes and Measures: The primary end point was grade 4 hemorrhage or grade 5 adverse events in the first year. Secondary end points were locoregional progression-free (LRPF) interval, distant metastasis-free (DMF) interval, progression-free survival (PFS), overall survival (OS), and other adverse events. Long-term toxic effects and clinical outcomes were reported due to the limited follow-up in the initial report for this trial and the importance of long-term outcomes when combining bevacizumab with chemoradiation. Results: Among 46 patients with NPC who were enrolled, 44 patients were analyzed (29 males [65.9%]; 23 Asian [52.3%], 2 Black [4.5%], and 16 White [36.4%]; 38 not Hispanic [86.4%]; median [IQR] age, 48.5 [39.0-56.0] years). There were 33 patients with a Zubrod performance status of 0, indicating that they were fully functional and asymptomatic (75.0%); 32 patients with a WHO histologic grade of IIb or III (72.7%); and 39 patients with stage III or IVB disease (88.6%). Among analyzed patients, 42 individuals received radiation therapy of 69.96 Gy or greater (95.5%; dose range, 65.72-70.00 Gy); 30 patients received 3 cycles of cisplatin (68.2%) with RT, and 31 patients received 3 cycles of bevacizumab with RT (70.5%); this was followed by 3 cycles of adjuvant cisplatin in 21 patients (47.7%), fluorouracil in 24 patients (54.5%), and bevacizumab in 23 patients (52.3%). No grade 4 hemorrhage or grade 5 AEs were reported in the first year or thereafter. Late grade 3 AEs occurred in 16 patients (36.4%), including 7 patients with dysphagia (15.9%), 6 patients with hearing impairment (13.6%), and 2 patients with dry mouth (4.5%). The 1- and 5-year rates of feeding tube use were 5 of 41 patients (12.2%) and 0 of 27 patients, respectively. There were 19 patients (43.2%) who progressed or died without disease progression (6 patients with locoregional progression [13.6%], 8 patients with distant progression [18.2%], and 5 patients who died without progression [11.4%]). The 5- and 7-year rates were 79.5% (95% CI, 67.6%-91.5%) and 69.7% (95% CI, 55.9%-83.5%) for OS, 61.2% (95% CI, 46.8%-75.6%) and 56.3% (95% CI, 41.5%-71.1%) for PFS, 74.9% (95% CI, 61.4%-86.6%) and 72.3% (95% CI, 58.4%-84.7%) for LRPF interval, and 79.5% (95% CI,66.4%-90.0%) for both times for DMF interval. Among 13 patients who died, death was due to disease in 8 patients (61.5%). Conclusions and Relevance: In this nonrandomized controlled trial, no grade 4 hemorrhage or grade 5 AEs were reported in the first year or thereafter among patients with NPC receiving bevacizumab combined with chemoradiation. The rate of distant metastasis was low although 89% of patients had stage III to IVB disease, suggesting that further investigation may be warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT00408694.

The collateral impact of the COVID-19 pandemic on HPV-positive oropharyngeal cancer diagnosis.

PURPOSE: We aim to assess the potential impact of the COVID-19 pandemic on diagnostic delays in HPV-positive oropharyngeal cancer (OPC), and to describe their underlying reasons. METHODS: All HPV + OPC referred to a tertiary cancer centre and diagnosed between June-December 2019 (Pre-Pandemic cohort) vs June-December 2020 (Pandemic cohort) were reviewed. TNM classification, gross-tumor-volumes (GTV) and intervals between sign/symptom onset and treatment initiation were compared between the cohorts. Reasons for delay (>6 months from onset of signs/symptoms to a positive biopsy of the primary tumor, or a delay specifically mentioned in the patient chart) in establishing the diagnosis were recorded per clinician's documentation, and categorized as COVID-related or non-COVID-related. RESULTS: A total of 157 consecutive HPV + OPC patients were identified (Pre-Pandemic: 92; Pandemic: 65). Compared to the Pre-Pandemic cohort, Pandemic cohort patients had a higher proportion of N2-N3 (32 % vs 15 %, p = 0.019) and stage III (38 % vs 23 %, p = 0.034) disease at presentation. The differences in proportions with > 6 months delay from symptom onset to establishing the diagnosis (29 % vs 20 %, p = 0.16) or to first treatment (49 % vs 38 %, p = 0.22) were not statistically different. 47 % of diagnostic delays in the Pandemic cohort were potentially attributable to COVID-19. CONCLUSION: We observed a collateral impact of the COVID-19 pandemic on HPV + OPC care through more advanced stage at presentation and a non-significant but numerically longer interval to diagnosis. This could adversely impact patient outcomes and future resource allocation. Both COVID-19-related and unrelated factors contribute to diagnostic delays. Tailored interventions to reduce delays are warranted.

Cigarette smoking cessation, duration of smoking abstinence, and head and neck squamous cell carcinoma prognosis.

BACKGROUND: Tobacco use is a major risk factor for developing head and neck squamous cell carcinoma (HNSCC). However, the prognostic associations with smoking cessation are limited. The authors assessed whether smoking cessation and increased duration of abstinence were associated with improved overall (OS) and HNSCC-specific survival. METHODS: Clinicodemographic and smoking data from patients with HNSCC at Princess Margaret Cancer Center (2006-2019) were prospectively collected. Multivariable Cox and Fine and Gray competing-risk models were used to assess the impact of smoking cessation and duration of abstinence on overall mortality and HNSCC-specific/noncancer mortality, respectively. RESULTS: Among 2482 patients who had HNSCC, former smokers (adjusted hazard ratio [aHR], 0.71; 95% CI, 0.58-0.87; p = .001; N = 841) had a reduced risk of overall mortality compared with current smokers (N = 931). Compared with current smokers, former smokers who quit >10 years before diagnosis (long-term abstinence; n = 615) had the most improved OS (aHR, 0.72; 95% CI, 0.56-0.93; p = .001). The 5-year actuarial rates of HNSCC-specific and noncancer deaths were 16.8% and 9.4%, respectively. Former smokers (aHR, 0.71; 95% CI, 0.54-0.95; p = .019) had reduced HNSCC-specific mortality compared with current smokers, but there was no difference in noncancer mortality. Abstinence for >10 years was associated with decreased HNSCC-specific death compared with current smoking (aHR, 0.64; 95% CI, 0.46-0.91; p = .012). Smoking cessation with a longer duration of quitting was significantly associated with reduced overall and HNSCC-specific mortality in patients who received primary radiation. CONCLUSIONS: Smoking cessation before the time of diagnosis reduced overall mortality and cancer-specific mortality among patients with HNSCC, but no difference was observed in noncancer mortality. Long-term abstinence (>10 pack-years) had a significant OS and HNSCC-specific survival benefit.

Clinical presentation and outcome of human papillomavirus-positive nasopharyngeal carcinoma in a North American cohort.

BACKGROUND: The objective of this study was to describe the clinical presentation and outcomes of human papillomavirus (HPV)-positive nasopharyngeal cancer (NPC) versus Epstein-Barr virus (EBV)-positive NPC and HPV-positive oropharyngeal cancer (OPC). METHODS: Clinical characteristics and presenting signs/symptoms were compared between patients who had viral-related NPC versus viral-related OPC treated with intensity-modulated radiotherapy from 2005 to 2020 and who were matched 1:1 (by tumor and lymph node categories, smoking, age, sex, histology, and year of diagnosis). Locoregional control (LRC), distant control (DC), and overall survival (OS) were compared using the 2005-2018 cohort to maintain 2 years of minimum follow-up. Multivariable analysis was used to evaluate the cohort effect. RESULTS: Similar to HPV-positive OPC (n = 1531), HPV-positive NPC (n = 29) occurred mostly in White patients compared with EBV-positive NPC (n = 422; 86% vs. 15%; p < .001). Primary tumor volumes were larger in HPV-positive NPC versus EBV-positive NPC (median volume, 51 vs. 23 cm3 ; p = .002), with marginally more Level IB nodal involvement. More patients with HPV-positive NPC complained of local pain (38% vs. 3%; p = .002). The median follow-up for the 2005-2018 cohort was 5.3 years. Patients who had HPV-positive NPC (n = 20) had rates of 3-year LRC (95% vs. 90%; p = .360), DC (75% vs. 87%; p = .188), and OS (84% vs. 89%; p = .311) similar to the rates in those who had EBV-positive NPC (n = 374). Patients who had HPV-positive NPC also had rates of LRC (95% vs. 94%; p = .709) and OS (84% vs. 87%; p = .440) similar to the rates in those who had HPV-positive OPC (n = 1287). The DC rate was lower in patients who had HPV-positive disease (75% vs. 90%; p = .046), but the difference became nonsignificant (p = .220) when the analysis was adjusted for tumor and lymph node categories, smoking, and chemotherapy. CONCLUSIONS: HPV-positive NPC and EBV-positive NPC seem to be mutually exclusive diseases. Patients who have HPV-positive NPC have greater local symptom burden and larger primary tumors but have similar outcomes compared with patients who have EBV-positive NPC or HPV-positive OPC.

Tumor-Naïve Multimodal Profiling of Circulating Tumor DNA in Head and Neck Squamous Cell Carcinoma.

PURPOSE: Circulating tumor DNA (ctDNA) enables personalized treatment strategies in oncology by providing a noninvasive source of clinical biomarkers. In patients with low ctDNA abundance, tumor-naïve methods are needed to facilitate clinical implementation. Here, using locoregionally confined head and neck squamous cell carcinoma (HNSCC) as an example, we demonstrate tumor-naïve detection of ctDNA by simultaneous profiling of mutations and methylation. EXPERIMENTAL DESIGN: We conducted CAncer Personalized Profiling by deep Sequencing (CAPP-seq) and cell-free Methylated DNA ImmunoPrecipitation and high-throughput sequencing (cfMeDIP-seq) for detection of ctDNA-derived somatic mutations and aberrant methylation, respectively. We analyzed 77 plasma samples from 30 patients with stage I-IVA human papillomavirus-negative HNSCC as well as plasma samples from 20 risk-matched healthy controls. In addition, we analyzed leukocytes from patients and controls. RESULTS: CAPP-seq identified mutations in 20 of 30 patients at frequencies similar to that of The Tumor Genome Atlas (TCGA). Differential methylation analysis of cfMeDIP-seq profiles identified 941 ctDNA-derived hypermethylated regions enriched for CpG islands and HNSCC-specific methylation patterns. Both methods demonstrated an association between ctDNA abundance and shorter fragment lengths. In addition, mutation- and methylation-based ctDNA abundance was highly correlated (r > 0.85). Patients with detectable pretreatment ctDNA by both methods demonstrated significantly worse overall survival (HR = 7.5; P = 0.025) independent of clinical stage, with lack of ctDNA clearance post-treatment strongly correlating with recurrence. We further leveraged cfMeDIP-seq profiles to validate a prognostic signature identified from TCGA samples. CONCLUSIONS: Tumor-naïve detection of ctDNA by multimodal profiling may facilitate biomarker discovery and clinical use in low ctDNA abundance applications.

Comparing unilateral vs. bilateral neck management in lateralized oropharyngeal cancer between surgical and radiation oncologists: An international practice pattern survey.

BACKGROUND: Management of the neck in oropharyngeal carcinoma varies due to a lack of clarity of patterns of lymphatic drainage and concern of failure in the contralateral neck. With recent advances in transoral surgical techniques, surgical management has become increasingly prevalent as the primary treatment modality. We compare international practice patterns between surgical and radiation oncologists. METHODS: A survey of neck management practice patterns was developed and pilot tested by 6 experts. The survey comprised items eliciting the nature of clinical practice, as well as patterns of neck management depending on extent of nodal disease and location and extent of primary site disease. Proportions of surgical and radiation oncologists treating the neck bilaterally were compared using the chi-squared statistic. RESULTS: Two-hundred and twenty-two responses were received from 172 surgical oncologists, 44 radiation oncologists, 3 medical oncologists, and 3 non-oncologists from 32 different countries. For tongue base cancers within 1 cm of midline (67% vs. 100%, p < 0.001), and for tonsil cancers with extension to the medial 1/3 of the soft palate (65% vs. 100%, p < 0.001) or tongue base (77% vs. 100%, p < 0.001), surgical oncologists were less likely to treat the neck bilaterally. For isolated tonsil fossa cancers with no nodal disease, both surgical and radiation oncologists were similarly likely to treat unilaterally (99% vs. 97%, p = NS). However, with increasing nodal burden, radiation oncologists were more likely to treat bilaterally for scenarios with a single node < 3 cm (15% vs. 2%, p < 0.001), a single node with extranodal extension (41% vs. 18%, p < 0.001), multiple positive nodes (55% vs. 23% p < 0.001), and node(s) > 6 cm (86% vs. 33%, p < 0.001). For tumors with midline extension, even with a negative PET in the contralateral neck, the majority of surgical and radiation oncologists would still treat the neck bilaterally (53% and 84% respectively). CONCLUSIONS: The present study demonstrates significant practice pattern variability for management of the neck in patients with lateralized oropharyngeal carcinoma. Surgical oncologists are less likely to treat the neck bilaterally, regardless of tumor location or nodal burden. Even in the absence of disease in the contralateral neck on imaging, them majority of practitioners are likely to treat bilaterally when the disease approaches midline.

Reduced-Dose Radiation Therapy for HPV-Associated Oropharyngeal Carcinoma (NRG Oncology HN002).

PURPOSE: Reducing radiation treatment dose could improve the quality of life (QOL) of patients with good-risk human papillomavirus-associated oropharyngeal squamous cell carcinoma (OPSCC). Whether reduced-dose radiation produces disease control and QOL equivalent to standard chemoradiation is not proven. PATIENTS AND METHODS: In this randomized, phase II trial, patients with p16-positive, T1-T2 N1-N2b M0, or T3 N0-N2b M0 OPSCC (7th edition staging) with ≤ 10 pack-years of smoking received 60 Gy of intensity-modulated radiation therapy (IMRT) over 6 weeks with concurrent weekly cisplatin (C) or 60 Gy IMRT over 5 weeks. To be considered for a phase III study, an arm had to achieve a 2-year progression-free survival (PFS) rate superior to a historical control rate of 85% and a 1-year mean composite score ≥ 60 on the MD Anderson Dysphagia Inventory (MDADI). RESULTS: Three hundred six patients were randomly assigned and eligible. Two-year PFS for IMRT + C was 90.5% rejecting the null hypothesis of 2-year PFS ≤ 85% (P = .04). For IMRT, 2-year PFS was 87.6% (P = .23). One-year MDADI mean scores were 85.30 and 81.76 for IMRT + C and IMRT, respectively. Two-year overall survival rates were 96.7% for IMRT + C and 97.3% for IMRT. Acute adverse events (AEs) were defined as those occurring within 180 days from the end of treatment. There were more grade 3-4 acute AEs for IMRT + C (79.6% v 52.4%; P < .001). Rates of grade 3-4 late AEs were 21.3% and 18.1% (P = .56). CONCLUSION: The IMRT + C arm met both prespecified end points justifying advancement to a phase III study. Higher rates of grade ≥ 3 acute AEs were reported in the IMRT + C arm.

Prognostic value of clinical and radiologic extranodal extension and their role in the 8th edition TNM cN classification for HPV-negative oropharyngeal carcinoma.

BACKGROUND/OBJECTIVES: We evaluate the performance between the TNM-8 versus TNM-7 cN-classification and explore the relative prognostic contribution of radiologic extranodal extension (rENE) for HPV-negative oropharyngeal cancer (HPV-OPC). MATERIALS/METHODS: All HPV- OPC treated with IMRT between 2005 and 2016 were included. cENE was defined as unambiguous "fixation" of a neck mass or "skin involvement" on clinical examination. rENE was recorded by re-reviewing pre-treatment CT/MR. Disease-free survival (DFS) stratified by cENE or rENE were compared. Multivariable analyses (MVA) calculated the adjusted hazard ratio (aHR) for the separate cENE and rENE attributes and their combination. A refined cN-category incorporating both cENE and rENE parameters was proposed. The performance of the revision was compared to TNM-8 and TNM-7. RESULTS: Of 361 HPV- OPC, 97 were cN0 and 264 were cN+ with 48 cENE+ and 72 rENE+ respectively. Median follow-up was 5.4 years. The 3-year DFS was lower in cENE+ vs cENE-negative (cENE-) (23% vs 45%; aHR = 1.68, p = 0.008) and rENE+ vs rENE-negative (rENE-) patients (29% vs 45%; aHR = 1.44, p = 0.037). The cENE+/rENE+ subset had the worse DFS vs cENE-/rENE+ or cENE-/rENE- (24%/37%/46%, p = 0.005). We propose a refined cN-category wherein any cENE-/rENE+ case is reclassified one N-stratum higher while any cENE+ case remains cN3b. The stage schema with the refined N-categorization outperformed TNM-8, and both outperformed TNM-7. CONCLUSIONS: cENE and rENE are both prognostic but the cENE+/rENE+ subset has the worst outcome. The TNM-8 cN-categories improves outcome prediction compared to the TNM-7. Incorporation of rENE into TNM-8 cN-categories may further augment performance.

Senescence, Necrosis, and Apoptosis Govern Circulating Cell-free DNA Release Kinetics.

The kinetics of circulating cell-free DNA (cfDNA) release may provide a real-time assessment of induced cell death. However, there is a limited understanding of the underlying biological rationale for cfDNA release following distinct treatments and cell death mechanisms. Here, we uncover a complex interplay between apoptosis, necrosis, and senescence in determining cfDNA release kinetics. Utilizing multiple in vitro and in vivo preclinical models, we show how cfDNA release is modulated through a combination of apoptotic and senescent triggers and inhibitors. Interestingly, we identify treatment-induced senescence as a previously unrecognized determinant of cfDNA kinetics that can counteract its release. Necrosis is the predominant cell death mechanism that consistently contributes to cfDNA release in response to ionizing radiation, and, surprisingly, apoptosis plays a comparatively minor role in some tumors. Based on our results, we propose a model to explain cfDNA release from cells over time, with important implications for future studies.

Considerations for head and neck oncology practices during the coronavirus disease 2019 (COVID-19) pandemic: Wuhan and Toronto experience.

The practices of head and neck surgical oncologists must evolve to meet the unprecedented needs placed on our health care system by the Coronavirus disease 2019 (COVID-19) pandemic. Guidelines are emerging to help guide the provision of head and neck cancer care, though in practice, it can be challenging to operationalize such recommendations. Head and neck surgeons at Wuhan University faced significant challenges in providing care for their patients. Similar challenges were faced by the University of Toronto during the severe acute respiratory syndrome (SARS) pandemic in 2003. Herein, we outline our combined experience and key practical considerations for maintaining an oncology service in the midst of a pandemic.

Privacy-preserving distributed learning of radiomics to predict overall survival and HPV status in head and neck cancer.

A major challenge in radiomics is assembling data from multiple centers. Sharing data between hospitals is restricted by legal and ethical regulations. Distributed learning is a technique, enabling training models on multicenter data without data leaving the hospitals ("privacy-preserving" distributed learning). This study tested feasibility of distributed learning of radiomics data for prediction of two year overall survival and HPV status in head and neck cancer (HNC) patients. Pretreatment CT images were collected from 1174 HNC patients in 6 different cohorts. 981 radiomic features were extracted using Z-Rad software implementation. Hierarchical clustering was performed to preselect features. Classification was done using logistic regression. In the validation dataset, the receiver operating characteristics (ROC) were compared between the models trained in the centralized and distributed manner. No difference in ROC was observed with respect to feature selection. The logistic regression coefficients were identical between the methods (absolute difference <10-7). In comparison of the full workflow (feature selection and classification), no significant difference in ROC was found between centralized and distributed models for both studied endpoints (DeLong p > 0.05). In conclusion, both feature selection and classification are feasible in a distributed manner using radiomics data, which opens new possibility for training more reliable radiomics models.

Prognostic importance of radiologic extranodal extension in HPV-positive oropharyngeal carcinoma and its potential role in refining TNM-8 cN-classification.

PURPOSE: This study examines outcome heterogeneity and potential to refine the TNM-8 cN-classification using radiologic extranodal extension (rENE) in a contemporary HPV-positive (HPV+) oropharyngeal carcinoma (OPC) cohort. METHODS: All HPV+ OPC treated with definitive IMRT from 2010-2015 were included. Pre-treatment CT/MR of cN+ cases were reviewed by a head-neck radiologist for rENE. Overall survival (OS) and disease-free survival (DFS) were compared between rENE-positive (rENE+) vs rENE-negative (rENE-). Multivariable analysis (MVA) for OS confirmed the prognostic value of rENE. Refined cN-classifications for new TNM staging proposals were evaluated against TNM-8 using established criteria. RESULTS: A total of 517 cN+ (rENE+: 97; rENE-: 420) and 41 cN0 cases were identified. The rENE+ proportion increased with rising N-category (N1/N2/N3: 11%/19%/84%, p < 0.001). Median follow-up was 5.1 years. Compared to rENE-, rENE+ patients had a lower 5-year OS (56% vs 85%) and DFS (46% vs 83%) overall, and in N1 (OS: 57% vs 89%; DFS: 51% vs 87%) and N2 subsets (OS: 45% and 76%; DFS: 33% vs 74%) (all p < 0.001). MVA confirmed the prognostic value of rENE for OS (HR = 3.86, p < 0.001) and DFS (HR = 3.89, p < 0.001). We proposed two new cN-classifications: Schema1 reclassified any N_rENE+ as New_N3; Schema2 reclassified N1_rENE+ as New_N2 and N2_rENE+ as New_N3. Stage incorporating either Schema1 (ranked 1st) or Schema2 (ranked 2nd) cN-categories outperformed TNM-8. CONCLUSION: This study confirms that rENE is prognostically important and facilitates understanding of known outcome heterogeneity within TNM-8 in HPV+ OPC patients. rENE is a promising parameter to refine the TNM-8 cN-classifications.

Plasma redox imbalance caused by albumin oxidation promotes lung-predominant NETosis and pulmonary cancer metastasis.

Neutrophil extracellular traps (NETs) promote cancer metastasis in preclinical models following massive exogenous inflammatory stimuli. It remains unknown whether cancer hosts under physiologic conditions experience NETosis and consequent metastasis. Here we show that plasma redox imbalance caused by albumin oxidation promotes inflammation-independent NETosis. Albumin is the major source of free thiol that maintains redox balance. Oxidation of albumin-derived free thiol is sufficient to trigger NETosis via accumulation of reactive oxygen species within neutrophils. The resultant NETs are found predominantly within lungs where they contribute to the colonization of circulating tumor cells leading to pulmonary metastases. These effects are abrogated by pharmacologic inhibition of NET formation. Moreover, albumin oxidation is associated with pulmonary metastasis in a cohort of head and neck cancer patients. These results implicate plasma redox balance as an endogenous and physiologic regulator of NETosis and pulmonary cancer metastasis, providing new therapeutic and diagnostic opportunities for combatting cancer progression.

Radiomic Biomarkers to Refine Risk Models for Distant Metastasis in HPV-related Oropharyngeal Carcinoma.

PURPOSE: Distant metastasis (DM) is the main cause of death for patients with human papillomavirus (HPV)-related oropharyngeal cancers (OPCs); yet, there are few reliable predictors of DM in this disease. The role of quantitative imaging (ie, radiomic) analysis was examined to determine whether there are primary tumor features discernible on imaging studies that are associated with a higher risk of DM developing. METHODS AND MATERIALS: Radiation therapy planning computed tomography scans were retrieved for all nonmetastatic p16-positive OPC patients treated with radiation therapy or chemoradiation therapy at a single institution between 2005 and 2010. Radiomic biomarkers were derived from each gross tumor volume. The biomarkers included 4 representative radiomic features from tumor first-order statistics, shape, texture, and wavelet groups, as well as a combined 4-feature signature. Univariable Cox proportional hazards models for DM risk were identified. The discriminative performance of prognostic univariable and multivariable models was compared using the concordance index (C-index). Subgroup analyses were performed. RESULTS: There were 300 HPV-related OPC patients who were eligible for the analysis. A total of 36 DM events occurred within a median follow-up period of 5 years. On univariable analysis, top results included the 4 representative radiomic features (C-index, 0.670-0.686; P < .001), the radiomic signature (C-index, 0.670; P < .001), tumor stage (C-index, 0.633; P < .001), tumor diameter (C-index, 0.653; P < .001), and tumor volume (C-index, 0.674; P < .001), which demonstrated moderate discrimination of DM risk. Combined clinical-radiomic models yielded significantly improved performance (C-index, 0.701-0.714; P < .05). In subgroup analyses, the radiomic biomarkers consistently stratified patients for DM risk, particularly for those cohorts with greater risks (C-index, 0.663-0.796), such as patients with stage III disease. CONCLUSIONS: Radiomic biomarkers appear to classify DM risk for patients with nonmetastatic HPV-related OPC. Radiomic biomarkers could be used either alone or with other clinical characteristics in the assignment of DM risk in future HPV-related OPC clinical trials.

Development and validation of a radiomic signature to predict HPV (p16) status from standard CT imaging: a multicenter study.

OBJECTIVES: Human papillomavirus (HPV) positive oropharyngeal cancer (oropharyngeal squamous cell carcinoma, OPSCC) is biologically and clinically different from HPV negative OPSCC. Here, we evaluate the use of a radiomic approach to identify the HPV status of OPSCC. METHODS: Four independent cohorts, totaling 778 OPSCC patients with HPV determined by p16 were collected. We randomly assigned 80% of all data for model training (N = 628) and 20% for validation (N = 150). On the pre-treatment CT images, 902 radiomic features were calculated from the gross tumor volume. Multivariable modeling was performed using least absolute shrinkage and selection operator. To assess the impact of CT artifacts in predicting HPV (p16), a model was developed on all training data (Mall) and on the artifact-free subset of training data (Mno art). Models were validated on all validation data (Vall), and the subgroups with (Vart) and without (Vno art) artifacts. Kaplan-Meier survival analysis was performed to compare HPV status based on p16 and radiomic model predictions. RESULTS: The area under the receiver operator curve for Mall and Mno art ranged between 0.70 and 0.80 and was not significantly different for all validation data sets. There was a consistent and significant split between survival curves with HPV status determined by p16 [p = 0.007; hazard ratio (HR): 0.46], Mall (p = 0.036; HR: 0.55) and Mno art (p = 0.027; HR: 0.49). CONCLUSION: This study provides proof of concept that molecular information can be derived from standard medical images and shows potential for radiomics as imaging biomarker of HPV status. Advances in knowledge: Radiomics has the potential to identify clinically relevant molecular phenotypes.

Radiation Therapy for Oropharyngeal Squamous Cell Carcinoma: American Society of Clinical Oncology Endorsement of the American Society for Radiation Oncology Evidence-Based Clinical Practice Guideline.

Purpose The American Society for Radiation Oncology (ASTRO) produced an evidence-based guideline on radiation therapy in oropharyngeal squamous cell carcinoma (OPSCC) that was determined to be relevant to the American Society of Clinical Oncology (ASCO) membership. After applying standard critical appraisal policy and endorsement procedures, ASCO chose to endorse the ASTRO guideline. Methods The ASTRO guideline was reviewed by ASCO content experts for clinical accuracy and by ASCO methodologists for developmental rigor. On favorable review, an ASCO Expert Panel was convened to review the guideline contents and recommendations. The ASCO guideline approval body, the Clinical Practice Guidelines Committee, approved the final endorsement. Results The ASCO Expert Panel determined that the ASTRO guideline recommendations, published in July 2017, are clear, thorough, and based upon the most relevant scientific evidence. ASCO endorsed the ASTRO guideline and added minor qualifying statements. Recommendations Recommendations for the addition of systemic therapy to definitive radiotherapy in the treatment of OPSCC, postoperative radiotherapy with and without systemic therapy following primary surgery of OPSCC, induction chemotherapy in the treatment of OPSCC, and the appropriate dose, fractionation, and volume regimens with and without systemic therapy in the treatment of OPSCC are outlined for a variety of disease stages and clinical scenarios. ASCO Endorsement Panel qualifying statements and minor modifications were made to the ASTRO recommendations. The staging system that is referenced in these guidelines is the American Joint Committee on Cancer Staging Manual, 7th edition. Additional information is available at: www.asco.org/head-neck-cancer-guidelines and www.asco.org/guidelineswiki .